Assessments included radiation dosimetry, kinetic modeling, test–retest variability (TRT) evaluation, and a dose occupancy evaluation using soticlestat, a selective CH24H inhibitor. Soticlestat is currently in phase 3 development for the treatment of seizures in Dravet syndrome and Lennox–Gastaut syndrome. Methods: In the dosimetry study, 5 participants (3 men) underwent serial whole-body scans to estimate organ-absorbed doses and effective doses of [18F]T-008 using OLINDA/EXM 1.1. For the kinetic modeling and TRT study, 6 participants  underwent two 210-min dynamic [18F]T-008 PET scans with arterial blood sampling. The regional total volume of distribution was estimated using a 1-tissue-compartment model, a 2-tissue-compartment model, and Logan graphic analysis. In the dose occupancy study, 11 participants  underwent 120-min scans at baseline and 2 time points (peak and trough) after receiving single oral doses of soticlestat (50–600 mg). The relationship between effect-site soticlestat concentration and brain occupancy was evaluated with a specially developed pharmacokinetic model and a saturable maximal occupancy model. Results: The estimated mean whole-body effective dose was 0.0292 mSv/MBq . [18F]T-008 entered the brain rapidly, with a distribution consistent with known CH24H distribution densities. The 2-tissue-compartment model and Logan graphic analysis best described the tracer kinetics. The mean TRT for estimating total volume of distribution was 7%–15%. Single doses of soticlestat in the range 50–600 mg resulted in occupancies of 64%–96% at 2 h and 11%–79% at 24 h. The estimated half-maximal effect-site concentration of soticlestat was 5.52 ng/mL. Conclusion: [18F]T-008 is a suitable PET radiotracer for quantitatively analyzing CH24H in the human brain. Using [18F]T-008 and PET, we demonstrated that soticlestat was brain-penetrant and established target engagement by displacing [18F]T-008 in a dose-dependent manner in the brain.This series of studies characterized [ Soticlestat is a selective CH24H inhibitor  that is 18F]T-008, a PET imaging radiotracer for CH24H that has previously demonstrated high selectivity and specificity in nonhuman primates  assessment, and evaluation of the effect of pharmacologic doses of soticlestat on in vivo binding of [18F]T-008 in the brain .Here, we report a series of clinical imaging studies with [primates . The stu18F]T-008  were performed according to the procedures described in U.S. Food and Drug Administration Investigational New Drug application 123966, using a commercial synthesizer, TRACERlab FX-FN . Details are provided in the supplemental materials .The radiolabeling and preparation of [18F]T-008, to model the tissue-specific kinetics of [18F]T-008 in the brain, and to establish target occupancy of soticlestat using [18F]T-008 and PET.There were 3 primary objectives: to determine the whole-body distribution and radiation dosimetry of T-008, vital signs , electrocardiography results, and results from clinical laboratory tests  were assessed.For each participant, before injection of T-008 dose of 340.2 ± 14.9 MBq (9.2 ± 0.4 mCi). Directly afterward they underwent PET : 9 whole-body passes were performed in succession, up to approximately 5.5 h , with scans from the tip of the head to the thighs at 9 bed positions. Urine samples were collected after the fifth, seventh, and ninth passes.Participants received an intravenous bolus [Methods for data acquisition and calculation of residence time  in source organs are presented in more detail in the supplemental materials –14.18F]T-008 at a dose of 326 ± 37 MBq (8.8 ± 1.0 mCi), dynamic PET scans were acquired over 3.5 h including a 30-min break after the first 90 min. Before any PET activities, a 3-dimensional T1-weighted MR image was acquired for each participant for anatomic identification and image processing. Image processing was performed with PMOD 3.405 (PMOD Technologies). The probabilistic volume-of-interest atlas  [18F]T-008 and was used to obtain an arterial input function (AIF) for kinetic modeling. The plasma free fraction (fP) was measured by ultrafiltration.Arterial blood samples were collected throughout the imaging period and analyzed for . Reliability was evaluated by assessing the intraclass correlation coefficient (ICC), defined as (between-participant mean square − within-participant mean square)/(between-participant mean square + within-participant mean square).Each participant received a baseline scan and 2 postsoticlestat (blocking) scans on days 1 and 2, respectively. Data were acquired dynamically over 120 min, an interval based on time-stability analysis of data from the kinetic modeling and TRT study.The first 2 participants received a single dose of soticlestat, 600 mg, as per the protocol. For each dosing cohort, a dose-level review meeting occurred to review the imaging occupancy results and safety data. The dose level and timing of the imaging were adjusted accordingly during the study.18F]T-008 metabolite-corrected AIF from these scans was used to model the AIF for the second blocking scan. Weights were based on the injected [18F]T-008 doses (IDs), as follows:Arterial blood was collected during the baseline and first blocking scans. The weighted average T-008 whole-body distribution data are provided in the supplemental materials.Overall mean absorbed doses and whole-body effective dose are summarized in 18F]T-008 readily entered the human brain and was ubiquitously distributed with high to moderate accumulation in the putamen; caudate nucleus; nucleus accumbens; pallidum; thalamus; frontal, occipital, parietal, insular, and temporal lobes; anterior and posterior cingulate; amygdala; and hippocampus. Accumulation was low in the brain stem and cerebellum. Peak uptake, expressed as SUV, was approximately 8 in the putamen about 30 min after injection. Washout was much faster in the cerebellum, in which uptake peaked up to 5 min after injection.[18F]T-008 was rapidly metabolized. Up to 27% of the parent compound remained at 60 min after injection. Subsequently, the parent fraction reached a plateau that was maintained at approximately 25% up to 210 min  was estimated to be 48% .T-008 was similar to that observed in the TRT study, with a mean of 30%  remaining at 60 min after injection, followed by a plateau at about 25% that was maintained up to 120 min. No major differences in [18F]T-008 metabolism between baseline and the first scan after soticlestat administration were observed. The mean fP was 41%  at baseline and 40%  after soticlestat administration, with no significant effect of soticlestat on fP. Furthermore, no trend was observed for fP as a function of soticlestat dose.The plasma metabolite profile of T-008 as a CH24H-specific radioligand, based on biodistribution, reproducibility, and target specificity, and assessment of radiation dosimetry and pharmacokinetic parameters.We report the first—to our knowledge—in vivo human PET studies conducted to clinically validate [18F]T-008 showed that the tracer was cleared via both hepatobiliary and renal routes, with no organ presenting an abnormally high uptake. The critical organ was the gallbladder, with the gallbladder wall receiving the highest mean absorbed dose. Although still at an acceptable level, the dose received by the gallbladder can be reduced through the intake of food or drink with a high fat content immediately after the PET scan to stimulate bile ejection , thus avoiding excessive arterial blood draws.Kinetic modeling results identified 2TC as the preferred model over 1TC for T-008. As such, the VND could not be obtained directly from any region of reference. Therefore, both CH24H occupancy and VND, when possible, were estimated directly from the occupancy plots on the basis of VT only. In the absence of a reference region, BPND values were calculated indirectly on the basis of VT and VND to allow for the estimation of regional occupancies, which presented a small SD. This calculation demonstrated that no brain region exhibited occupancy significantly different from the global occupancy estimates. Because VND could not be accurately determined for the 2 participants who received soticlestat, 50 mg, neither BPND nor the regional occupancies could be obtained. Missing regional occupancy data could explain the differences in the EC50 estimates when compared with the corresponding occupancy estimates, modeled from high-uptake regions such as the caudate or putamen.Oral dosing with soticlestat resulted in substantial blocking in all brain regions, including the cerebellum, as is in line with the results in nonhuman primates . At highOccupancy ranged from 11% at trough plasma levels to 98% at peak plasma levels. These measurements were both dose- and time-dependent, increasing with increasing dose and decreasing with time. Many of the pharmacokinetic samples collected during the dose occupancy study did not contain measurable levels of soticlestat, particularly at low occupancy values. Consequently, limited pharmacokinetic data were available and a pharmacokinetic model was developed to describe the complex nonlinear pharmacokinetics of soticlestat, using available data from single- and repeated-dose studies. The model was adequate in characterizing the pharmacokinetic data used in the analysis .max model that used the predicted effect-site soticlestat concentrations provided a better fit for the data because there appeared to be a temporal lag between plasma soticlestat concentrations and brain occupancy values at later time points. This lag suggests that the plasma drug concentration was not in equilibrium with that at the effect site, namely the site of action where the initial pharmacologic response is produced.The model-predicted soticlestat concentrations were subsequently used to develop a concentration–occupancy model in which they were linked to brain occupancy values. A saturable E50 value estimated with the predicted effect-site concentration (5.52 ng/mL) did not shift significantly  from the EC50 value estimated with the plasma data (3.01 ng/mL) when using a simplified version of the Emax model .Interestingly, the EC18F]T-008 is a useful PET radiotracer for in vivo imaging of CH24H in the human brain. Kinetic modeling results indicated that the quantification of [18F]T-008 requires arterial sampling because no suitable reference region lacking CH24H could be found. The estimated mean effective dose suggests that an acceptably low radiation exposure is associated with [18F]T-008 imaging in human participants and is consistent with values reported for other PET radiotracers currently used in human studies (max model. Findings from these studies were used to guide the schedule and dosing for clinical trials with soticlestat.Data reported here demonstrate that [ studies . SoticleThis study was funded by Takeda Pharmaceutical Co. Ltd. Terry Brown, Shining Wang, Wei Yin, and Johannes Tauscher are employees of Takeda Pharmaceutical Co. Ltd. and own stock or stock options. Cristian C. Constantinescu is an employee of Invicro, which was contracted by Takeda Pharmaceutical Co. Ltd. to conduct the study. Olivier Barret and Danna Jennings are former employees of Invicro. Under the direction of the authors and funded by Takeda Pharmaceutical Co. Ltd., Aimee Jones and Erin Aldera of Oxford PharmaGenesis, Oxford, U.K., provided medical writing support for this publication. Editorial assistance in formatting, proofreading, copyediting, and fact-checking was also provided by Oxford PharmaGenesis. No other potential conflict of interest relevant to this article was reported.


Hepatic sinusoidal obstruction syndrome (SOS) is a severe and life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a multi-center retrospective study to evaluate the utility of our ultrasonographic scoring system for the diagnosis of SOS (HokUS-10) in predicting SOS-related mortality (SOS-RM). We analyzed a total of 42 patients who developed SOS after HSCT. The cumulative incidences of SOS-RM, non-relapse mortality (NRM), and overall survival at day 180 after the diagnosis of SOS were 26.4%, 28.8% and 54.5%, respectively. The area under the receiver operating characteristic curve analysis showed that the optimal cut-off value of HokUS-10 total score to predict SOS-RM was 8 points after the treatment of SOS. In the individual HokUS-10 score, ascites and portal vein flow-related scores (PV mean velocity and PV flow direction) after the treatment of SOS were shown as significant risk factors for SOS-RM. Our study suggested that US findings after the treatment can predict the treatment outcomes for SOS. Its risk depends on patient characteristics, disease status, conditioning, and prior history of treatments4. Severe SOS is a risk for multi-organ failure and high mortality5. Therefore, rapid diagnosis and early intervention are critical to improve treatment outcome against SOS. We have established an ultrasonography (US) -based scoring system for the diagnosis of SOS: the Hokkaido US-based scoring system (HokUS-10), consisting of 10 parameters including hepatomegaly, gallbladder wall thickening, ascites, portal vein (PV) and paraumbilical vein (PUV) dilatation, and abnormal blood flow signals in the PV and PUV6. However, the prognostic impact of US findings on treatment outcomes for SOS has never been elucidated.Hepatic sinusoidal obstruction syndrome (SOS) is a severe and life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT), characterized by hepatomegaly with quadrant pain, jaundice, and ascites7 or EBMT criteria3 and evaluated HokUS-10 before and after the treatment . Informed consent was obtained from each patient for participation in the study. For patients who could not obtain informed consent, we disclosed the information about this clinical study on the website of our institution and guarantee the opportunity for refusal (opt-out). Since this study is a retrospective study, opt-out disclosure eliminates the need for patient consent.We conducted a multicenter retrospective study to evaluate the association of HokUS-10 scores and treatment outcomes, including engraftment, acute graft-versus-host disease (GVHD), relapse, non-relapse mortality (NRM), overall survival (OS), and SOS-related mortality (SOS-RM) in patients with hematological malignancies who received HSCT between March 2010 and June 2021 in Hokkaido University or Sapporo Hokuyu Hospital, and were clinically diagnosed SOS as modified Seattle criteriant Table . The cut9/L on the first of 3 consecutive days, and platelet engraftment was defined as an absolute platelet count > 2.0 × 1010/L without transfusion support on the first of 7 preceding days. Acute GVHD was graded according to the consensus criteria7. Non-relapse mortality (NRM) was defined as death due to any cause other than relapse. Relapse and causes of death were determined based on the decision of each clinician. SOS-RM was defined as death due to organ failure by SOS without relapse9. Overall survival (OS) was calculated from the day of SOS diagnosis, with patients alive at the time of last follow-up censored. NRM, relapse and SOS-RM were also calculated from the day of SOS diagnosis. HokUS-10 was evaluated in each institution, and was performed central review at Hokkaido University for this study.Neutrophil engraftment was defined as an absolute neutrophil count > 0.5 × 10U-test for continuous variables, Kaplan–Meier method, Log-rank test, and Cox proportional hazard model for OS, Gray’s test for engraftment, GVHD, relapse, NRM, and SOS-RM, and Fine and Gray competing risk regression model for NRM and SOS-RM. The cut-off value of HokUS-10 to predict SOS-RM was determined based on receiver operating characteristic (ROC)-curve analysis. Results were expressed as hazard ratio (HR) with the 95% confidence interval (95% CI). A value of P < 0.05 was used to determine statistical significance. All analyses were performed with EZR , which is a graphic user interface for R 10.Statistical analysis was performed using Mann–Whitney The authors confirm that this study was conducted in accordance with relevant national, international, and institutional guidelines. The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.Patient and transplant characteristics in this study are shown in Table Neutrophil engraftment and platelet engraftment was achieved in 95.2% (95% CI 82.3–98.8%) and 58.4% 95% CI 41.5–72.0%), respectively Fig. . The cum.5–72.0%,P = 0.019, Fig. P = 0.077, Fig. P = 0.10, Fig. First, we evaluated the association of SOS-RM with total score of HokUS-10 before and after the treatment of SOS. The median days of HokUS-10 evaluation after the start of treatment was 15, ranging from 7 to 21. The median score of HokUS-10 was 6, ranging from 4 to 11, before the treatment, and 5, ranging from 1 to 11, after the treatment. Changes in an individual score of HokUS-10 before and after the treatment were shown in Fig. P = 0.20, after: < 5 points, 13.3% vs ≥ 5 points, 33.6%, P = 0.31). We determined the optimal cut-off value of HokUS-10 to predict SOS-RM. The area under the ROC curve analysis showed that only 8 points after the treatment of SOS became moderate accuracy to predict day 180 SOS-RM  and OS  (Table P = 0.005). On the other hand, no significant risk factor for NRM was identified and EBMT severity was only identified as a significant risk factor for OS   Table . MultivaP = 0.006) before the treatment of SOS, and ascites , PV mean velocity , PV flow direction  after the treatment of SOS as risk factors for SOS-RM.We also evaluated the association of an individual HokUS-10 score before and after the treatment of SOS with SOS-RM Table . Univari11, with the high sensitivity (100%) and specificity (95.8%)6. The advantage of US for the diagnosis of SOS is its ability to detect blood flow abnormalities responsible for the pathogenesis of SOS. Gallbladder wall thickening, dilatation of PUV, or appearance of PUV flow signal reflects congestion of the cystic vein returning to the PV system downstream of sinusoids. However, it remained to be elucidated whether HokUS-10 could predict treatment outcomes for SOS. In this study, we showed that high total scores (≥ 8 points) and ascites and PV flow-related scores (PV mean velocity and PV flow direction) after the treatment of SOS was significantly associated with SOS-RM. EBMT criteria also emphasizes the US findings including ascites and decrease in velocity or reversal of the portal flow as the essential ultrasound evidence of SOS3. Especially, PV flow is converged from the stomach, intestines, pancreas, spleen, and gallbladder, which plays an important role in transporting amino acids absorbed in intestines, hormones produced in pancreas, and decomposition products excreted from spleen to liver. Failure to improve PV flow after the treatment of SOS may reflect extensive sinusoidal obstruction, suggesting poor prognosis. Previous studies also showed the association of PV flow abnormality with poor prognosis in patients with hepatic cirrhosis13. Prediction of treatment outcomes for SOS using HokUS-10 scoring system may help to determine timing of cessation of SOS treatment.This multi-center retrospective study showed that HokUS-10 scores 2 weeks after the initiation of SOS treatment was associated with treatment outcomes. HokUS-10 was established based on US finding reported by Lassau et al.15. Treatment outcomes were comparable between patients who received DF and rTM in this study as well.Our study has several limitations, including a retrospective design, small sample size. The day of HokUS-10 evaluation after the treatment of SOS was not fixed. Cases with rapid progression after the diagnosis of SOS were not included, because only cases who could evaluate HokUS-10 about 2 weeks after the start of treatment were included in this study. rTM was not used outside Japan, although the previous study showed comparable therapeutic effect between rTM and DFNevertheless, our study showed the efficacy of US findings for the prediction of treatment outcomes for SOS. Larger studies should be conducted to confirm our findingsand establish a novel scoring system using US findings for treatment outcomes of SOS.Supplementary Figure 1.Supplementary Figure 2.Supplementary Table 1.Supplementary Table 2.Supplementary Table 3.Supplementary Information 6.


Therefore, this study aimed to assess the anti-amnesic and antidepressant-like potential of JJGW08, a novel arylpiperazine alkyl derivative of salicylamide with strong antagonistic properties at 5-HT1A and D2 receptors and weak at 5-HT2A and 5-HT7 receptors in rodents. First, we investigated the compound’s affinity for 5-HT6 receptors using the radioligand assays. Next, we assessed the influence of the compound on long-term emotional and recognition memory. Further, we evaluated whether the compound could protect against MK-801-induced cognitive impairments. Finally, we determined the potential antidepressant-like activity of the tested compound. We found that JJGW08 possessed no affinity for 5-HT6 receptors. Furthermore, JJGW08 protected mice against MK-801-induced recognition and emotional memory deficits but showed no antidepressant-like effects in rodents. Therefore, our preliminary study may suggest that blocking serotonin receptors, especially 5-HT1A and 5-HT7, might be beneficial in treating cognitive impairments, but it requires further investigation.Memory impairments constitute a significant problem worldwide, and the COVID-19 pandemic dramatically increased the prevalence of cognitive deficits. Patients with cognitive deficits, specifically memory disturbances, have underlying comorbid conditions such as schizophrenia, anxiety, or depression. Moreover, the available treatment options have unsatisfactory effectiveness. Therefore, there is a need to search for novel procognitive and anti-amnesic drugs with additional pharmacological activity. One of the important therapeutic targets involved in the modulation of learning and memory processes are serotonin receptors, including 5-HT Memory is fundamental to everyday life, and cognitive impairments significantly deteriorate normal functioning. The World Health Organization reports that dementia, a loss of cognitive functioning, affects more than 55 million people worldwide and constitutes the seventh leading cause of death . The pre1A, 5-HT6, and 5-HT7 receptors are important for learning and memory as they are localized in brain areas involved in cognitive processes .  in mice . Furthermice 1A and/oriewed in . Studiesagonists ,80 as weists pentoxy}benzamide hydrochloride (JJGW08) was synthesized in the Department of Organic Chemistry and Technology, Faculty of Chemical and Engineering and Technology, Cracow University of Technology. The synthesis and biological properties of the compound were described earlier . ip) 30 min before each behavioral test. The chemicals used in radioligand studies, i.e., methiothepin , were dissolved in saline. MK-801  was dissolved in saline and administered ip 15 min before experiments. The control groups received 0.9% NaCl solution ip 30 min prior to testing. The studied compound was tested in in vivo experiments at the dose range of 0.625–2.5 mg/kg, which was selected based on our previous experiments [JJGW08 was dissolved in saline  and administered intraperitoneally  in a controlled environment , adequate humidity (40–60%), 12 h light/dark cycle) with All experimental procedures were performed between 8 a.m. and 4 p.m. Animals were selected randomly for treatment groups and each group consisted of 8–10 mice. All injections were administered in a volume of 10 mL/kg. The animals were used only once in each test, and immediately after each experiment, they were euthanized.Procedures involving animals were conducted according to current European Community and Polish legislation on animal experimentation and were approved by the Local Ethical Committee for Animal Experiments at the Jagiellonian University in Krakow .6 receptor. The assay procedures were conducted according to the slightly modified method described by Sałaciak and colleagues [Radioligand binding assays were performed using membranes from CHO-K1 cells, which were stably transfected with the human 5-HTlleagues .–10 to 10–5 M. The inhibitory constant (Ki) was estimated using GraphPad Prism 5.0 . A single assay was performed with each compound concentration in duplicate, and the whole assay was repeated in three independent experiments. Inhibition constants (Ki) were calculated according to the equation of Cheng and Prusoff [Binding experiments were performed in 96-well microplates, and the reaction mix included a solution of the tested compound, radioligand, and diluted membranes or the tissue suspension. Specific assay conditions for each target are shown in  Prusoff .ip 30 min before the acquisition trial. To induce memory impairments, MK-801 (0.125 mg/kg) was administered ip 15 min before the experiment. Control groups were injected ip with saline or with saline and MK-801. The step-through passive avoidance task was performed according to the method previously described ,68. The ip 30 min before the familiarization phase to assess its influence on recognition memory. To induce memory disturbances, MK-801 (0.125 mg/kg) was administered ip 15 min before the experiment. Control groups were injected ip with saline or with saline and MK-801.The test was performed according to the method described earlier ,88 and cThe experiment was performed on mice according to the method described by Porsolt et al. and as previously described ,89. MiceThe experiment was carried out on mice according to the method described by Steru et al. and as previously described ,91. The The locomotor activity of mice was measured as previously described , using apost hoc or two-way ANOVA with repeated measures followed by Bonferroni post hoc test. One-sample t-test was used to analyze the results of the object recognition task. In cases when assumptions for normal distribution of data was not fulfilled, we used Kruskal–Wallis with Dunn’s post hoc test. A value of p < 0.05 was considered to be significant. The results are presented as means ± SD (standard deviation) or medians ± interquartile range . The normality of data sets and their homogeneity were determined using D’Agostino and Pearson and Brown–Forsythe tests, respectively. The comparisons between experimental and control groups were performed by one-way ANOVA followed by Newman–Keuls 1A and D2 receptors and weak antagonist of 5-HT2A and 5-HT7 receptors with the potential antipsychotic- and anxiolytic-like activity, possessed no affinity for 5-HT6 receptors, and no antidepressant-like activity in rodents. Furthermore, the compound did not impair mice’s long-term emotional or recognition memory acquisition and protected mice against the MK-801-induced recognition and emotional memory deficits. Therefore, our preliminary study may suggest that a blockade of serotonin receptors, especially 5-HT1A and 5-HT7 receptors might be beneficial in treating cognitive impairments.In this study, we found that JJGW08, a novel arylpiperazine alkyl derivative of salicylamide, which is a strong antagonist of 5-HT


Previous studies have declared that baseline lymphocyte count is associated with COVID-19-related death. However, whether dynamic lymphocyte change over time affects prognosis in COVID-19 patients is unknown. This study aims to investigate the significance of lymphocyte count during the progression of the disease in COVID-19 patients.P-value of less than 0.05 (two-sided).The retrospective cohort study recruited COVID-19 patients at the First People’s Hospital of Jiangxia District in Wuhan from January 7, 2020, to February 28, 2020. The demographics, medical histories, results of the blood routine test, and patients’ outcomes were collected. We utilized a generalized additive mixed model to compare trends in lymphocyte count over time among survivors and non-survivors, with an adjustment for potential confounders. The statistical analysis used R software and EmpowerStats. Significance was determined at a 9/L daily. After adjusting for several covariables, the increasing value remained at 0.0731 × 109/L per day.A total of 532 patients were included in the study. Overall, there were 29/532 in-hospital deaths (5.45%). Lymphocytes declined over time in the non-survivor group and increased in the survivor group in the first 10 days of hospitalization. Within 10 days after admission, lymphocyte count increased in the survivor group and decreased in the non-survivor group. The difference in lymphocyte counts between survivors and non-survivors increased by an average of 0.0732 × 10In the early stage, lymphocyte count can dynamically reflect the pathophysiological changes in COVID-19 patients. An early decrease in lymphocyte count is associated with mortality in COVID-19 patients. The coronavirus disease 2019 (COVID-19) pandemic is the most severe infectious disease outbreak this century, causing millions of infections and deaths worldwide. While the pandemic has primarily abated in many regions, seasonal epidemics and periodic pandemics remain a constant threat and cause significant mortality , some ma+ T cells, and decreased C3 could predict the mortality of COVID-19 patients [Dysregulation of the immune system is directly linked to disease severity in COVID-19 patients . Immunocpatients . A meta-This study recruited 1066 patients diagnosed with COVID-19 at the First People’s Hospital of Jiangxia District in Wuhan between January 7, 2020, and February 28, 2020. Patients who meet these criteria would be excluded: (1) those still hospitalized by February 29, 2020 (345 cases); (2) those who died on admission (5 cases); (3) those with malignancy (6 cases); (4) those with a history of gastrointestinal surgery (7 cases); (5) those baseline lymphocyte counts were missing (31 cases); (6) those lymphocyte counts detected only once (143 cases). Finally, 532 patients were included. This study was approved by the Medical Ethics Committee of the First People’s Hospital of Jiangxia District in Wuhan. Written informed consent was not required because the data were anonymous, and the study was retrospective observational.The demographics, medical histories, and outcomes were collected from the electronic hospital information system. Blood samples were collected in the morning after an overnight fast, and blood routine tests were conducted. We got white blood cell count, neutrophil count, lymphocyte count, and platelet count from the hospital information system. Lymphocyte count was rechecked at variable intervals.http://www.R-project.org, The R Foundation) and EmpowerStats . Significance was determined at a P-value of less than 0.05 (two-sided).Categorical data are displayed in absolute counts (percentages), while measured data are presented as mean ± standard deviation. In the baseline characteristics of survivors and non-survivors Table , sex, hyP < 0.001). Compared with the survivors, the counts of white blood cells  and neutrophils  were higher in non-survivors. In addition, the counts of baseline lymphocytes  and platelets  were lower in non-survivors than in survivors. Regarding comorbidities, it was observed that non-survivors were more likely to have a history of hypertension (P < 0.001) and diabetes (P < 0.001). The differences in lymphocyte count between survivors and non-survivors at different time points are presented in Table P < 0.001). Similarly, female survival patients had a significantly higher lymphocyte count on the 14-15th day than non-survivors (P = 0.023).The demographic and clinical characteristics at baseline are shown in Table 9/L daily. After adjusting for several covariables , the increasing value remained at 0.0731 × 109/L per day, indicating the result was stable.Figure 9/L per day.This study investigated the trends of lymphocyte count during the progression of the disease in COVID-19 patients. It was found that lymphocytes declined over time in non-survivors and increased in survivors in the early hospitalization stage. Within 10 days after admission, the difference in lymphocyte count between the two groups increases by 0.0731 × 10Many studies have explored the correlation between lymphocytes and COVID-19 hospitalization outcomes. Xiong et al. have indicated that COVID-19 patients, particularly in severe cases, tend to have a lower count of lymphocytes . FurtherOur study has several strengths. First, the present study is more practical than the previous studies that only examined baseline lymphocyte count. Second, as the lymphocyte count was measured repeatedly in this study, using GAMM was appropriate in elucidating the correlation between the fluctuation of lymphocyte count and the clinical outcomes. Third, we used strict statistical adjustments to reduce potential confounding, and the result remains stable after adjusting for several covariables.Our research has some limitations. First, the study only included Chinese COVID-19 patients, so it may not be generalized to people from other countries. Second, this is an observational cohort study, so causal conclusions cannot be drawn. Further study is needed to investigate whether improving immunity to increase lymphocyte count can improve the prognosis of COVID-19 patients. Third, the sample size of this study was relatively small. However, the sample size is sufficient to get a conclusion. Future studies with larger sample sizes are needed to determine the association of changes in lymphocyte count over time and in-hospital mortality in COVID-19 patients.In the early stage, lymphocyte count can dynamically reflect the pathophysiological changes in COVID-19 patients. An early decrease in lymphocyte count is associated with mortality in COVID-19 patients. This finding may indicate that COVID-19 patients with decreased lymphocytes after admission need more attention.


Besides this, mean miR-138.5p values were lower in those patients with NEDA-3 at 2 years (p = 0.033), and miR-146a.5p and miR-126.3p were higher in patients with CDP progression at 2 years  are promising biomarkers in multiple sclerosis (MS). This study aims to investigate the association between a preselected list of miRNAs in serum with therapeutic response to Glatiramer Acetate (GA) and with the clinical evolution of a cohort of relapsing–remitting MS (RRMS) patients. We conducted a longitudinal study for 5 years, with cut-off points at 2 and 5 years, including 26 RRMS patients treated with GA for at least 6 months. A total of 6 miRNAs from a previous study  were selected for this analysis. Clinical relapse, MRI activity, confirmed disability progression (CDP), alone or in combination (No Evidence of Disease Activity-3) (NEDA-3), and Expanded Disability Status Scale (EDSS), were studied. After multivariate regression analysis, miR-9.5p was associated with EDSS progression at 2 years (β = 0.23; 95% CI: 0.04–0.46;  There is a great interest and a growing need to develop biomarkers in multiple sclerosis (MS), to better predict the clinical evolution of the disease, the therapeutic response to the different disease-modifying treatments, and to better understand the mechanisms of progression. MicroRNAs are small, highly conserved non-coding RNA molecules, between 20 and 25 nucleotides. They participate in RNA silencing and post-transcriptional modification of gene expression , and regWe previously conducted a cross-sectional investigation to correlate the miRNAs profile expression with the Expanded Disability Status Scale (EDSS), cognitive function, and brain volume status in a cohort of MS treated with glatiramer acetate (GA) . This isIn this study, we aimed to continue that research and analyze the correlation between the statistically associated miRNAs found in our previous work with the clinical evolution in the follow-up of these patients.We conducted a longitudinal study during a follow-up term of 5 years, with cut-off points at 2 and 5 years. Inclusion criteria: relapsing–remitting multiple sclerosis (RRMS) patients treated with GA for at least 6 months attending the MS unit of Torrejón University Hospital and Getafe University Hospital in Madrid. Participants were reviewed clinically every 6 months as routine clinical practice, and every time that there was a relapse or any other clinically relevant situation. MRIs were performed every year as routine clinical practice. Those patients that reached the criteria of GA failure were changed to other disease-modifying treatments, as physician criteria, but continued in the study. Confirmed disability progression (CDP) was defined as a 6-month confirmed EDSS increase of ≥1.5 points if basal EDSS was 0; a 6-month confirmed EDSS increase of ≥1 point if basal EDSS was between 1 and 5.0; and a 6-month confirmed EDSS increase of ≥0.5 points if basal EDSS was ≥5.5. Magnetic resonance imaging (MRI) of the brain was performed one month before the beginning of glatiramer acetate treatment and every year since treatment initiation in 1.5T scanners. The sequences collected for this study were: axial proton density T2-weighted imaging, axial fluid-attenuated inversion recovery (FLAIR) T2, axial T2-weighted imaging, and T1-weighted imaging with gadolinium (Gd) enhancement. To cover the entire brain with contiguous axial sections, a slice thickness of 5 mm was performed. MRI activity was defined as ≥1 gadolinum-enhancing lesion and/or ≥2 new or enlarging T2 lesions. No Evidence of Disease Activity-3 (NEDA-3) was defined as not having CDP, MRI activity, or any relapse. ®, Franklin Lakes, NJ, USA), centrifuged at 920× g for 15 min at room temperature to separate serum and stored at −80 °C until RNA extraction. Before using the frozen serum for nucleic acid purification, we thaw it at room temperature. To remove cryoprecipitates, we centrifuge 300 μL thawed serum samples for 5 min at 3000× g and 4 °C, and we transfer 200 μL of supernatant to a new tube. Cell-free total RNA was extracted using the miRNeasy Serum/PlasmaAdvanced Kit  according to the manufacturer’s protocol. During the RNA extraction process, the UniSp2, UniSp4, and UniSp5 RNA Spike-in mix  was added to have a control for the quality of the RNA isolation. The total RNA was reverse transcribed using miRCURY LNA RNA kit  following the manufacturer’s instructions that generate universal cDNA templates for all miRNAs present in the sample. The synthetic UniSp6 RNA spike-in  was added to each sample during this process to have a control for the quality of the cDNA synthesis; and the reaction was performed in the Veriti™ thermal cycle . Prepared complementary DNAs were stored at −20 °C until use. We performed the miRCURY LNA miRNA QC PCR Panel  to analyze the robustness of the RNA isolation process and the quality of isolated miRNA. The panel contains matching locked nucleic acid (LNA) PCR assays for detection of: the RNA Spike-In mix ; the spike-ins UniSp6 andcel-miR-39-3p (not added in our experiments) to monitor cDNA synthesis; theUniSp3 IPC  to check if the qPCR was successful; four potential endogenous: miR-103-3p, miR-191-5p, miR-30c-5p, and miR-124-3p; andmiR-451a and miR-23a-3p that serve as hemolysis marker. MiRNA-specific quantification was performed using miRCURY LNA SYBR Green kit  according to the manufacturer’s instructions, in a LightCycler 96 instrument . We performed the miRCURY LNA miRNA Custom PCR Panels using only the samples with successful results in the miRCURY LNA miRNA QC PCR Panel. A total of 6 miRNAs statistically associated with clinical disability and brain atrophy in a previous work [Peripheral blood samples were collected from each enrolled patient in redtop vacutainer tubes without additives , alone or in combination (NEDA-3) was studied with a non-parametric test (U Mann–Whitney). Statistical significance was set at p ≤ 0.05. Statistical Package for Social Sciences, version 19.0  was used for statistical analysis. We described numerical variables expressed as with median and interquartile range and categorical variables as percentages. The correlation between miRNAs and EDSS progression was determined using backstep multivariate regression. Only the 6 microRNAs were included in the multivariate regression. Other variables were not included due to the small and homogeneous group. The tolerance limit was established at 0.01. The statistical significance for variable exclusion (POUT) for the sequential analysis was defined at We included 26 patients. The sample was composed of a typical early RRMS population, with female predominance, young age, and mild disability . There wNEDA-3 at 2 and 5 years was achieved by 70.8% and 56.5% of the patients, respectively. At the end of the study, only 20.81% of the patients remained on GA, while 42.3% were classified as therapeutic failure, and 30.8% had changed due to other reasons (side effects or patient preferences). There was one loss of follow-up .p = 0.047)  . We did = 0.047) . p = 0.033). We also found an association between higher values of miR-146a.5p and miR-126.3p and CDP progression at 2 years   . We did ctively) . ®, Barcelona, Spain), which was centered on MS pathology and cognitive dysfunction. These aspects would be more related to degeneration than to inflammation. These results would highlight the importance of these miRNAs in the pathogenic mechanism of neurodegeneration in this disease. In this study, we have corroborated some findings of a previous work . From thRobust evidence exists with mir-9.5p and miR-146.5p. In our previous work, miR-146.5p was positively and negatively associated with EDSS and Symbol Digit Modalities Test (SDMT), respectively. In this study, we also found higher values of these miRNAs in patients with CDP. MiR-146.5p has been consistently found upregulated in MS, both in different samples  ,17,18, aMiRNA-9.5p is a proinflammatory molecule that could play a pathogenic role in MS through several mechanisms, such as facilitating M1 macrophage reaction , increasMicroRNA 126.3p is located in endothelial cells and participates mainly in angiogenesis and cell migration ,34. TherMicroRNA 138.5p is a potent tumor suppressor that targets many different genes related to apoptosis, proliferation, invasion, and migration ,41,42. IFinally, we did not find any relationship with any microRNAs at 5 years of follow-up. This lack of association could be explained by methodological reasons because of a greater heterogeneity after that time of evolution. p < 0.05 deserve to be exposed and discussed, mainly given the multiple and coherent results obtained, especially with mir-146a.5p and with mir-9.5p. Finally, it will be necessary to replicate these results in larger and independent cohorts to confirm the effects of these microRNAs in MS and validate their applicability to monitor the progression of the disease and their utility as serum biomarkers.We are aware of some limitations and weaknesses of our study. First of all, the study was conducted on a small number of participants. This was an exploratory study, and we think that we could overcome this limitation thanks to the great homogeneity of our study population and with a preselection of the target miRNAs through a systems biology approach that enabled us to reduce the number of miRNAs to be studied in such a small sample. This methodology was proven effective and adequate in a previous study . In the This article reinforces the implication of microRNAs in the pathogenesis and evolution of multiple sclerosis. It would be of great interest to further investigate the role of these microRNA in this disease to elucidate their possible utility as prognostic biomarkers, predictors of response to disease-modifying treatments, and even as therapeutic agents.


This work investigated the effect of different valence states of phosphorus-containing compounds on thermal decomposition and flame retardancy of polyethylene terephthalate (PET). Three polyphosphates—PBPP with +3-valence P, PBDP with +5-valence P and PBPDP with both +3/+5-valence P—were synthesized. The combustion behaviors of flame-retardant PET were studied and the structure–property relationships between the phosphorus-based structures with different valence states and flame-retardant properties were further explored. It was found that phosphorus valence states significantly affected the flame-retardant modes of action of polyphosphate in PET. For the phosphorus structures with +3-valence, more phosphorus-containing fragments were released in the gas phase, inhibiting polymer chain decomposition reactions; by contrast, those with +5-valence phosphorus retained more P in the condensed phase, promoting the formation of more P-rich char layers. It is worth noting that the polyphosphate containing both +3/+5-valence phosphorous tended to combine the advantage of phosphorus structures with two valence states and balance the flame-retardant effect in the gas phase and condensed phase. These results contribute to guiding the design of specified phosphorus-based structures of flame-retardant compounds in polymer materials. Poly  (PET) is used in all aspects of life because of its excellent corrosion resistance, ease of processing, and excellent mechanical properties ,2,3. HowTherefore, many scholars have devoted themselves to developing PET composites with excellent flame-retardant properties. Phosphorus-based flame retardant was considered an excellent alternative to halogen-containing flame retardant because of its low toxicity and high flame-retardant efficiency. Kilinc  used difAt the same time, in order to ensure that the mechanical properties of the compound will not be greatly affected during processing, more and more PFRs are receiving attention, and polyphosphonate plays a major role . Some reHowever, the change of structure leads to differences in the valence state of phosphorus, which further affects the proportion of flame-retardant mechanisms in the condensed and gas phases ,15,16. TIn this work, PBPP, PBPDP and PBDP with different phosphorus valence states were synthesized and used in PET to analyze the effect of different phosphorus valence states on the flame-retardant mechanism.n about 20,000 g/mol.Phenylphosphonic Dichloride (PPD), Petroleum ether and Dichloromethane were provided by Beijing Innochem Technology Co., Ltd. . 4,4′-isopropylidenediphenol (BPA), and Phenyl dichlorophosphate (PCDP) were provided by Shanghai Aladdin Biochemical Technology Co., Ltd. . Triethylamine was provided by Tianjin FuChen chemical Co., Ltd. PET  with M2. At the end of the reaction, Petroleum ether was used for reprecipitation to get the final product. The synthesis process of the three polyphosphates was similar, with yields of 87%, 81% and 86%, respectively.The synthesis of flame retardants was carried out by changing the reaction of different phosphorus-containing dichloride and BPA (0.05 mol). The detail process of the reaction is shown in Before processing, PET and flame retardants were dried in a vacuum oven at 160 °C for 12 h. The test sample was processed in the torque rheometer at 270 °C, and then processed into splines by a tablet press according to the test standard. The addition of flame retardants in all PET composites was 8 wt.%, and the dimensions of the samples were 100 mm × 100 mm × 30 mm.Cone calorimeter test was carried out by FTT0007  according to ISO 5660:2015 standard.Thermogravimetric analysis (TGA) was carried out by a STA 8000 thermogravimetric analyzer . The temperature range was 50 °C to 700 °C and the heating rate was 20 °C/min.A thermogravimetry-Fourier transform infrared (TG-FTIR) test was carried out on a STA 8000 simultaneous thermal analyzer . The temperature range was 50 °C to 700 °C and the heating rate was 20 °C/min.The microscopic pictures of carbon residues were taken by a Phenom Prox scanning electron microscope (SEM) .−1.The Fourier transform infrared (FTIR) spectroscopy was carried out by a Nicolet iN10MX-type spectrometer  in the range of 4000–500 cmThe Hot-Stage Fourier transform infrared was performed on a LNP96-S/iS50 spectrometer .The pyrolysis of flame retardants was carried out by GCMS-QP 2010 Plus GC–MS with a PYR-4A pyrolyzer .−1 was attributed to the adsorption of P=O. Two absorption bands at 1200 and 958 cm−1, corresponding to the vibration of P-O-C bonds, can also be observed clearly. The peak at 3061 cm−1 corresponded to the Ar-H. Moreover, absorption bands at 1364 and 1408 cm−1 corresponded to the methyl bending vibrations [1H NMR spectrum of PBPP, peaks at 7.2–8.0 ppm were from the aromatic ring peaks of a phosphorous-containing side group, and signals at 7.0–7.2 ppm corresponded to the aromatic ring peaks of bisphenol A. The 1H NMR spectra of PBDP were different from those of PBPP. The aromatic ring peaks of a phosphorous-containing side group in PBDP appeared in 7.0–7.5 ppm. Additionally, the 1H NMR spectrum of PBPDP was a combination of PBPP and PBDP. Meanwhile, in the 31P NMR spectrum of PBPDP, there were two peaks, which corresponded to the P-O-Ar (12.64 ppm) and P-Ar (16.33 ppm) [1H SSNMR and 31P SSNMR, three flame retardants were successfully synthesized.The structural characterization of PBPP, PBPDP and PBDP is shown in .33 ppm) . As indic , which indicated that the carbon formation ability of polyphosphate was hardly affected by the valence states of phosphorus.The thermal stability of polymers is an important property in the process. TGA was used to test the thermal stability of samples in nitrogen and air with the results shown in 2 atmosphere was also studied  and listed in c values of three polyphosphates, there was a big difference in the synergistic charring ability with PET. As shown in c value of 23.7 wt.% at 700 °C, but this ability decreased as the partial +5-valence phosphorus was replaced by +3-valence ones, which indicated that +5-valence phosphorus was more likely to react with the matrix through transesterification with ester chains due to its more P-O-C bonds, forming P-containing crosslinking structures in the condensed phase, thus improving the carbon formation ability of PBDP composite. Moreover, the Rmax (the maximum rate of weight loss) of PET composites showed an opposite trend to that of the flame retardants. That may be because the polyphosphate containing more unstable P-O-C bonds perhaps decomposed earlier, so giving a lower Rmax. On the other hand, after polyphosphates were introduced to PET, +5-valence phosphorus acted more in the form of phosphoric acid or analogues in the condensed phase during the decomposition process, which promoted the dehydration and transesterification of PET chains and accelerated the formation of char layers.W: The content of the additions in the composites.R: The residue result after TGA test.The thermal stability of pure PET, PBDP/PET, PBPDP/PET and PBDP/PET composites under N studied . All polhosphate ,20,21. H2, while the values decreased to 603.6 kW/m2, 468.9 kW/m2 and 408.4 kW/m2 for PBDP/PET, PBPDP/PET and PBDP/PET, respectively. It was not difficult to find that with the increase of +5-valence phosphorus content, PHRR of composites decreased gradually, which might be due to the influence of different phosphorus-containing structures on the flame-retardant mechanism, more specifically on the quality of residual carbon in the condensed phase. THR showed the total heat release from the material during combustion and the trend of THR was similar to that of HRR . As PBPP was added, the FGI value of PBPP/PET decreased to 6.0 kW/(m2·s), which indicated that PBPP can effectively reduce the risk of fire. What was more, PBPDP/PET (4.7 kW/(m2·s)) and PBDP/PET (4.8 kW/(m2·s)) exhibited much lower FGI values, which indicated that flame retardants with +5-valence phosphorus exhibited higher fire safety performance in real fires [Fire growth index (FGI=PHRR/t-PHRR) was used to evaluated the fire hazards . The FGIal fires .2Y values in all PET compounds was due to the suppression of PET composite combustion. In addition, compared with the av-COY value of PET, only that of PBPP/PET rose [The smoke release during combustion is also considered an important influence in fire safety. In general, more char residue means that more decomposition fragments are retained in the condensed phase rather than released to the gas phase. As shown in PET rose , which p31P NMR spectrum of PBPDP. As shown in It should be noted that there seems to be some interaction between the two different valence states of phosphorus. The theoretical cone data of PBPDP/PET were calculated according to the proportion of two different phosphorus elements in the Additionally, three important flame-retardant effects  were calculated by Equations (1)–(3) according to the cone test values to evaluate the main flame-retardant modes of action. The results are listed in As shown in The macro- and micro-surface morphology of residues after the cone calorimetry test were investigated. As shown in In addition, the residual carbon after the cone volume test was analyzed elementally by X-ray photoelectron spectroscopy (XPS). Element contents, the reserved and released phosphorus (P) contents were calculated and shown in −1, -C=O at 1762 cm−1 and a C-H bond at 2956 cm−1, and the relative absorption strength of these peaks started to decrease at 350 °C and almost disappeared at 400 °C. In −1, corresponding to the P-O-Ar stretching vibration in PBDP/PET and PBPDP/PET, and the peak intensity increased obviously with the increase of +5-valence phosphorus content [ content ,26. This2 peaks at 2360 cm−1, CO peaks at 2180 cm−1, C-C bands at 1598 and 1508 cm−1, and phosphorus-containing species peaks at 1255, 1190 and 962 cm−1. However, the variation of peak intensity with temperature was obviously different. PBPP showed no obvious absorption peak before 525 °C, and reached the peak rapidly at 550 °C, while PBDP began to decompose in advance at 475 °C, and the absorption peak gradually increased to the peak, which was as same as the TGA curves. Moreover, it was observed that the absorption peak of P-O-C in PBPP was significantly stronger than that in PBPDP and PBDP, which indicated that the polyphosphate with +3-valence phosphorus can release more phosphorus-containing species with a quenching effect, thus mainly playing a gas-phase flame-retardant effect.TG-FTIR tests were performed to analyze the gas products of the PET composites, and the results are shown in m/z = 47 (PO•) and 63 (PO2•) were mainly attributed to the cleavage of phosphorus-containing compounds. Additionally, due to the different structure of phosphate, R can be divided into a benzene ring (m/z = 78) and phenol (m/z = 94) [/z = 94) . On the −1, hydrocarbon at 1280–1470 cm−1, CO2 at 2373–2354 cm−1, -C=O at 1762 cm−1 and CO at 2233–2144 cm−1. Moreover, most of the gaseous products of the three PET composites were the same as those of PET. It should be noted that a new absorbance peak of phosphorus-containing structures (P-O-C) appeared in TGA-FTIR of PBPP/PET, while with the decrease of 3-phosphorus content in flame retardants the absorbance peaks gradually decreased, and eventually disappeared in PBDP/PET. In addition, the changes of P-O-C release intensity in 2 free radicals in the gas phase, so as to play a stronger role in gas-phase action [−1) and hydrocarbon (1280–1470 cm−1) fragments were usually released into the gas phase as volatile combustible fuels to sustain the combustion process [The changes of gas-phase products were also detected by TGA-FTIR, and the results are shown in e action ,28. Duri process . From FiBased on the analysis of gas- and condensed-phase products of flame retardants and composites, the effects of different phosphorus valence states on the flame-retardant mechanism of PET are summarized in In this work, three polyphosphates with different phosphorus valences were synthesized to investigate the effect of different phosphorus valences on their flame-retardant mechanism in PET. The results showed that the valence structure affected the proportion of phosphorus exerting flame-retardant roles in the gas/condensed phases. PBPP with +3-valence phosphorus played more pivotal roles in the gas phase, which generated more P-containing free radicals during the combustion process to eliminate H· and HO· free radicals, thereby inhibiting the continuous progress of combustion reactions. On the other hand, PBDP with +5-valence phosphorus was more likely to react with the matrix through transesterification with ester chains due to its greater P-O-C bonds, forming P-containing crosslinking structures in the condensed phase, thus improving the amount and quality of char residue. It should be noted that the flame-retardant test results of PBPDP containing both +3- and +5-valence phosphorus were better than the theoretical calculated values, which indicated that there was a synergistic flame-retardant effect between the two different valence states of phosphorus which tended to combine the advantages of phosphorus in these two valence states.


Prostate cancer radiation therapy (RT) to the pelvis is one of the curative approaches for patients with localized prostate cancer. Most patients treated with prostate RT experience some degree of radiation-induced lower urinary tract symptoms (RI-LUTSs). These symptoms may have a negative impact on patients’ quality of life after treatment. The aim of our prospective study was to determine if prophylactic α-blockers improved RI-LUTSs in men undergoing prostate RT. Overall, we found that there were no important effects of prophylactic α-blockers on RI-LUTSs. Therefore, treating prostate cancer patients preventatively with α-blockers may cause additional drug toxicity and financial burden without significantly improving their urinary symptoms. This trial was registered with ClinicalTrials.gov under the registration number NCT02220829.p = 0.40). There were no significant differences in IPSSs between the study arms in the intention-to-treat (ITT) analysis at baseline, the last day of RT, and 4 and 12 weeks post-RT. Conclusion: Prophylactic α-blockers were not effective at significantly reducing RI-LUTSs in prostate cancer patients treated with EBRT. Treating patients with α-blockers at the onset of RI-LUTSs will avoid unnecessary drug exposure and toxicity.Purpose: The present phase III randomized trial assessed the efficacy of prophylactic versus therapeutic α-blockers at improving RI-LUTSs in prostate cancer patients receiving external beam radiotherapy (EBRT). Methods: A total of 148 prostate cancer patients were randomized 1:1 to receive either prophylactic silodosin on day one of EBRT or the occurrence of RI-LUTSs. LUTSs were quantified using the international prostate symptom score (IPSS) at regular intervals during the study. The primary endpoint was the change in the IPSS from baseline to the last day of radiotherapy (RT). Secondary endpoints included changes in IPSS from baseline to 4 weeks and 12 weeks after the start of RT. Results: Patient demographics, baseline IPSS, and prescribed radiation doses were balanced between arms. On the last day of RT, the mean IPSS was 14.8 (SD 7.6) in the experimental arm and 15.7 (SD 8.5) in the control arm ( Prostate cancer is the second most common cancer among men worldwide . In the RI-LUTSs are commonly managed by administering α-blockers which act by inhibiting the activity of α-adrenergic receptors in the urethra and bladder neck. These receptors are G-protein coupled receptors (GPCRs) that, when stimulated by a catecholamine, induce the contraction of smooth muscle fibers. Although these receptors exist as three subtypes , α-1A adrenoceptors are the primary mediators of smooth muscle tone in the bladder, prostate, and urethra ,6,7. ThePresently, several α-blockers are available and have demonstrated variable selectivity for different α-1 adrenoceptor subtypes ,9. AmongGiven the lack of prospective clinical trials, we designed a phase III randomized controlled trial (RCT) to determine whether prophylactic α-1-blockers would decrease the rate and intensity of LUTSs, improve their recovery post-EBRT and maximize patients’ quality of life during and after RT. The trial was conducted at the Jewish General Hospital located in Montreal, Quebec, Canada. The trial was approved by the institutional ethics review board and was conducted in compliance with the guidelines for the Good Clinical Practice of the International Conference on Harmonization and the principles of the Declaration of Helsinki. All the patients provided written informed consent prior to their enrollment. Eligible patients were 18 years of age or older with a confirmed diagnosis of localized adenocarcinoma of the prostate, treated primarily with EBRT with or without HDR BT boost. Patients with a history of radical prostatectomy, metastatic (M1), or locally advanced (T4) disease invading surrounding organs in the pelvic cavity, severe hepatic (Child–Pugh score ≥ 10) or renal impairment (CCr < 30 mL/min) were excluded from the study. The computer-generated randomization process was conducted centrally. Upon successful enrolment into the trial, treatment allocation was performed in an unblinded manner. Patients received 8 mg of silodosin PO daily either prophylactically or therapeutically upon symptom onset only. Patients randomized in the prophylactic α-blocker group would take the medication starting on Day 1 of RT for a total duration of six months: 8 mg daily for four months, and then 8 mg every other day for the last two months. During the screening period, patient demographics and relevant medical history were gathered. Blood samples were collected for the assessment of liver function  and kidney function . In addition, initial LUTSs were evaluated through the IPSS questionnaire, which was subsequently repeated at pre-specified time points: four weeks after the start of RT, on the last day of RT, and monthly thereafter for six months. The IPSS questionnaire was also repeated at the nine- and twelve-month marks after the start of RT. While post-void residual urine tests were recommended during and after RT if indicated by the treating physician, they were not mandatory. The IPSS is a modified version of the American Urological Association symptoms index (AUA-SI) . It contThe primary outcome was a change in mean IPSS from baseline to the last day of RT. Secondary outcomes included a change in mean IPSS from baseline to 4 weeks and 12 weeks post-RT initiation, as well as the rate of return to baseline 3 months post-treatment.To assess the difference in the pre-specified outcomes between study arms, we fitted a linear regression model to all participants’ IPSS measures during the course of the trial. The main analysis was an intention-to-treat (ITT) analysis, with the study arm included as a predictor in the model. The model also included time since randomization as a categorical predictor and an interaction term in order to assess the interaction between the study arm and time. The correlation between repeated IPSS measures on the same participant was accounted for by assuming an unstructured covariance structure across observations, estimated using residual restricted maximum likelihood and empirical (“sandwich”) estimators. This covariance structure was selected because IPSS scores are expected to increase during the trial and then return to baseline levels over time, so other covariance structures assuming an equal or declining correlation over time were inappropriate for this analysis. Differences in the IPSS scores between arms and over time were estimated using model coefficients. The significance of predictor variables in the model was assessed using t and F statistics. We also performed an as-treated analysis, comparing all patients who received prophylactic α-blockers to those who did not receive medication prophylactically (either did not receive medication or received it at the onset of RI-LUTSs). For this analysis, we refitted the linear regression model using treatment received as a predictor instead of the study arm.In another exploratory analysis, we fitted a linear model to assess the association between the receipt of an α-blocker prescription and IPSS scores over time in the control arm. Due to the smaller number of observations in this analysis, a heterogeneous compound symmetry covariance structure was used to model within-subject correlation. All statistical analyses were performed using SAS software, version 9.4 . In total, 148 participants were recruited from January 2016 to November 2020, with 921 observations included in the analysis . There wp = 0.77). The scores increased in both the experimental and control groups to 14.8 (SD 7.6) and 15.7 (SD 8.5), respectively, by the end of RT. These changes were important, as assessed by a type III test for the effect of time (p < 0.0001). However, there were no significant differences between the two groups at the end of RT (p = 0.40). The IPSS increase from baseline to RT end was smaller in the experimental arm than in the control arm, but the −1.3 difference in score change from baseline was not significant . The as-treated analysis showed similar results (p = 0.13). At baseline, the mean IPSS was 10.8 (standard deviation [SD] 7.3) in the experimental arm and 10.4 (SD 7.2) in the control arm . There w results , with thp = 0.13). In both groups, the mean IPSS declined after the end of RT. While the 3-month mean IPSSs appeared lower than baseline in both arms, the confidence intervals overlapped (p = 0.17). Based on the type III test of fixed effects, the arm effect (p = 0.28) and the arm-by-time interaction effect (p = 0.84) were not statistically significant in the ITT analysis, suggesting there was no evidence that the prophylactic intervention had a different effect than standard care on the evolution of IPSS scores over time.At 4 weeks post-RT start, in the ITT analysis, the mean IPSSs rose to 14.1 (SD 6.2) and 16.1 (SD 8.0) in the experimental and control groups, respectively . Howeverp = 0.03) in favor of the arm receiving prophylactic α-blockers was identified (p < 0.0001), the group effect (p = 0.29) and the group-by-time interaction effect (p = 0.84) were not significant. Overall, the as-treated analysis yielded nearly similar results to the ITT analysis with the IPSS increasing from baseline within each group at 4 weeks post-RT start and RT end and returning close to baseline as early as three months after treatment initiation. However, a single important difference of −3.4 in IPSS at 4 weeks post-RT start  compared to those who did not (n = 45). However, these differences were not statistically significant in the overall type III test for the medication effects (p = 0.09). A subgroup analysis limited to the control arm (N = 76) was performed . The meap = 0.49, p = 0.47) and high-stage settings  at all time points.Exploratory analyses, whereby participants were stratified per prostate volume (PV) and T-stage, were also conducted. In an as-treated analysis restricted to participants with PVs <50 cc, a difference of −4.3 between groups in favor of prophylaxis was identified at 4 weeks post-RT initiation (95%CI −8.4 to −0.3) . Hence, RI-LUTSs can arise during and following prostate RT . Most paAlthough α-blockers are known to help alleviate LUTSs in patients undergoing BT, there have been no dedicated retrospective or prospective studies on its prophylactic use during prostate EBRT to our knowledge. Merrick et al. found that administering prophylactic α-blockers prior to LDR-BT can mitigate LUTSs . Furtherp = 0.25). Therefore, the four-week results could be attributable to chance from multiple testing rather than a consequence of prophylactic medication use. In the event that this result was not due to chance, it could suggest that prophylactic α-blockers were temporarily beneficial for LUTSs during RT in men with PVs <50 cc, similar to other published data [Our as-treated analysis yielded similar results to the ITT analysis, finding no significant difference in changes in IPSSs between the two groups at all time points except at 4 weeks into RT in favor of the treatment arm. Should it not be due to chance, this sole significant result may be clinically relevant ,20. Simihed data ,22,23. Ihed data . This phIf we exclude the participants who received prophylactic α-blockers pre-BT, about 60% of patients analyzed in Arm 2 did not receive a therapeutic prescription for silodosin at any point during or after RT. Prescribing α-blockers to all patients undergoing RT may unnecessarily expose them to unwarranted drug toxicity and financial burden. In fact, depending on the prescribed medication, adverse effects can include retrograde ejaculation, dizziness, or orthostatic hypotension ,26.Our study has some limitations. After performing a post hoc power calculation for a two-sided two-sample t-test on paired differences, we concluded the study would have a 20% chance to detect a difference of 1.3 with an α-level of 0.05. The low power is due to the effect size being small relative to the standard deviations in IPSS scores between participants. However, our study had an 80% chance to detect an IPSS difference of 3.3 with the same α-level. The Measurement Committee of the American Urological Association (AUA) defined the minimal clinically important difference (MCID) for an improvement of LUTSs as a −3.1 difference in IPSS ,20. In oFurthermore, the assessment of medication adherence was not ideal. Patients self-reported compliance during follow-ups. While refills were also monitored through medical records, the pills were not manually counted. Hence, a self-reporting bias may exist. While there is no gold standard for measuring adherence, the combination of two corroborative methods may have been more reliable .Our study demonstrates that prophylactic silodosin administration does not significantly decrease RI-LUTSs in patients receiving EBRT for prostate cancer. We, therefore, recommend initiating therapeutic α-blockers upon symptom onset. Consequently, this practice would improve efficacy, avoid treatment futility in the preventative setting, and spare prostate cancer patients from unnecessary toxicities.


On multivariate analysis, only NT-proBNP (log)  remained as an independent predictor. Conclusion: NT-proBNP is an independent predictor of all-cause mortality in a contemporary cohort of PAH-CHD patients. The role of CRP and uric acid should be further assessed in future studies.Background: About 5–10% of adults with congenital heart disease (ACHD) will develop pulmonary arterial hypertension (PAH), which is associated with significant mortality. Studies on risk factors for poor outcome in a contemporary cohort of these patients with PAH associated with CHD (PAH-CHD) are rare. Methods: In this retrospective, single-center study, adult patients with the diagnosis PAH-CHD who had at least one contact as an outpatient or inpatient at the German Heart Centre Munich during the period January 2010–September 2019 were included. Patients with PAH without a CHD were excluded. The primary endpoint was all-cause mortality. Results: Altogether, 158 patients  were included in the study. A pre-tricuspid shunt was present in 17.7%, other shunts in 51.3%, PAH associated with complex CHD in 22.8%, and segmental PAH in 8.2%. An NT-proBNP measurement at baseline was available in 95 patients (60.1%). During a median follow-up of 5.37 years [IQR 1.76–8.63], the primary endpoint occurred in 10 patients (6.7%). On univariate analysis, CRP (log) ,  Tremendous advances in the treatment of children with congenital heart disease (CHD) have been made in the fields of pediatric cardiology, cardiovascular surgery, and intensive care medicine in the last decades. As a consequence, nowadays it is expected that more than 90% of children with CHD will reach adulthood . HoweverTherefore, the aim of our study was to describe risk factors for an unfavorable outcome in a contemporary cohort of PAH-CHD patients, including all variants.This investigation was conducted as a retrospective, single-center study. All adult patients (>18 years of age) with the diagnosis PAH-CHD who had at least one contact as an outpatient or inpatient at the German Heart Centre Munich during the study period January 2010–September 2019 were included. Patients with PAH without an underlying diagnosis of CHD were excluded.The start of follow-up was the first contact during the study period, while the end of the follow-up period was either the last contact during the study period or the date of death if the patient died during the study period.As previously described, PAH-CHD was established and confirmed by echocardiography, cardiac MRI, and/or cardiac catheterization . The undDemographic data and information on medical as well as surgical history were retrieved from hospital records. The New York Heart Association classification (NYHA) was used to assess symptomatic status. Left and right ventricular systolic function was graded based on the results of routine transthoracic echocardiograms as normal, mildly, moderately or severely impaired, as previously described . ArrhythLaboratory values retrieved from medical records at the time of the baseline visit included hemoglobin, hematocrit, N-terminal pro-B type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), creatinine, uric acid, and bilirubin.The primary end-point was all-cause mortality. Cause of death was retrieved from hospital records.t-test was used for comparison between groups for continuous variables, while the Chi-square test was used for categorical variables. The association between variables and the primary endpoint was assessed with univariate Cox proportional hazards analysis. Significant variables (p < 0.05) from the univariate analysis were subsequently included in a multivariate model in a stepwise fashion. Cut-off values for significant variables from the multivariate Cox proportional hazards analysis were derived using the Youden index with a receiver operating characteristics (ROC) curve. Kaplan–Meier curves and log-rank tests were used to compare survival  between patients with values below and above the cut-off of significant variables. All tests were performed two-sided and, for all analyses, a p-value < 0.05 was considered statistically significant.Statistical analyses were performed with the software SPSS version 28  and MedCalc version 20.210 . Continuous variables are presented as mean ± standard deviation or median (interquartile range) and categorical variables as number (percentage). The Mann–Whitney U test or Student’s Altogether, 158 patients  were included in the study. A pre-tricuspid shunt was present in 17.7%, other shunts in 51.3%, PAH associated with complex CHD in 22.8%, and segmental PAH in 8.2%. Out of the 158 patients, 85 (53.8%) were on advanced PAH therapies at baseline. More information regarding the baseline characteristics is presented in At least one hospitalization occurred in 80 patients (53.7%). Out of these, 29 were unplanned/emergency admissions. The reasons for these unplanned hospitalizations were worsening heart failure in 14, arrhythmias in 13, chest pain in one and infection in another one.During a median follow-up of 5.37 years [IQR 1.76–8.63], the primary endpoint occurred in 10 patients (6.7%). The cause of death was cardiac in four patients, septicemia in three, and unknown in the remaining three. When comparing patients that have died during the study period with those alive at the end of follow-up regarding their baseline characteristics, patients who died were more likely to be in NYHA class IV .The univariate analysis for the whole cohort revealed no significant predictor for the primary endpoint .p = 0.090), sex (p = 0.429), type of congenital heart defect (p = 0.436), presence of Down syndrome (p = 0.987), follow-up duration (p = 0.182), or mortality (p = 0.510). Additionally, there was also no significant difference for NT-proBNP between patients with pre-tricuspid shunts (1868 ± 1875 ng/L), other shunt lesions (1219 ± 2430 ng/L), and PAH-CHD associated with complex CHD . Therefore, a second analysis regarding the predictors of the primary end-point was carried out solely in the cohort with an available NT-proBNP measurement at baseline. A comparison of laboratory values between those patients in whom the primary endpoint occurred and those in which it did not is presented in p = 0.022), CRP (p = 0.019), and uric acid (p = 0.010) at baseline.However, laboratory values were not included in this analysis because they were not available for the whole cohort. An NT-proBNP measurement at baseline was available in 95 patients (60.1%). The primary endpoint occurred in 7 (7.4%) out of these 95 patients. There was no significant difference between patients with an NT-proBNP measurement at baseline and those without regarding age (p = 0.037), NT-proBNP (log) , and uric acid  were predictors of the primary endpoint (p = 0.0196) remained as an independent predictor in the model  , endpoint . On multhe model .The area under the receiver operating characteristics curve for NT-proBNP was 0.761 . The cutp < 0.01; In patients in whom NT-proBNP was above the cut-off value, survival was diminished  are established biomarkers that are utilized in various forms of cardiovascular diseases, especially for the diagnosis of heart failure . They caInterestingly, CRP was a predictor of all-cause mortality in the univariate analysis. CRP is an acute-phase protein that is synthesized by hepatocytes in response to cytokines and functions as an easily available and widely used marker to assess inflammation in clinical practice . Its assUric acid was also a predictor of outcome in the univariate analysis. Uric acid, the final product of purine metabolism, is gaining increasing importance in the evaluation of cardiovascular disease . It is h2, and a ratio of right atrial to left atrial area ≥ 1.5 [Other predictors of outcome besides laboratory parameters have been identified in previous studies of PAH-CHD patients. Moceri et al. assessed echocardiographic predictors of outcome in patients with Eisenmenger syndrome, excluding those with complex CHD . They inea ≥ 1.5 . This coea ≥ 1.5 . Unfortuea ≥ 1.5 .Kempny and colleagues assessed whether the six-minute walk test distance was predictive of the outcome of mortality in Eisenmenger syndrome patients . AltogetThe mortality of the PAH-CHD cohort in the study from Scognamiglio et al. was higher 22%) compared to the mortality in the current cohort of 6.7% 2% compar. FurtherA limitation of our study is its retrospective nature with the associated obvious drawbacks inherent to this type of study. For example, variables such as NT-proBNP were not available in all patients. Additionally, the objective measures of exercise capacity such as the six-minute walk test were not regularly performed. Furthermore, the cause of death was not available in three patients.In conclusion, NT-proBNP is an independent predictor of all-cause mortality in a contemporary cohort of PAH-CHD patients. The role of CRP and uric acid in combination with other prognostic parameters should be further assessed in future studies.


As a novel lipoprotein ratio, baseline low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (LHR) is closely related to the clinical outcomes of acute coronary syndromes (ACS) after percutaneous coronary intervention. However, the pathophysiological impact of achieved LHR (aLHR) on the evolution of non-culprit lipid-rich plaques has not been systematically explored.Between September 2013 and December 2018, ACS patients with both baseline and 1-year follow-up optical coherence tomography (OCT) examinations were included in current study. They were divided into two groups according to the median value of aLHR at 1 year.p = 0.025) and higher prevalence of thin-cap fibroatheroma (TCFA)  and CLIMA-defined high-risk plaques  in the high aLHR group at 1 year. Compared with other serum lipid indexes, aLHR showed the best robust correlation with the evolution of plaque vulnerability in both unadjusted and adjusted analyses. Cut-off value of aLHR to predict the progression of maximal lipid arc and FCT was 1.51. In the adjusted model, aLHR ≥1.51 was an independent predictor of TCFA  at 1 year.Overall, 132 patients with 215 lipid-rich plaques were enrolled, with a median aLHR: 1.62. There were thinner fibrous cap thickness (FCT) (133.3 [70.0–180.0] µm vs. 160.0 [100.0–208.3] µm, aLHR correlates well with the evolution of lipid-rich plaques and vulnerable phenotypes at 1-year follow-up, which might be an important and convenient serum indicator in the secondary prevention of ACS. Dyslipidemia plays an important role in the occurrence, development and secondary prevention of acute coronary syndromes (ACS) . Many stDue to the high resolution and specific recognition of lipid components in-vivo, optical coherence tomography (OCT) has been widely used in the process of coronary interventions. It can not only quantitatively assess luminal features of targeted lesions, but also the lipid arc and fibrous cap thickness (FCT), which are vital features of plaque vulnerability and closely related to adverse clinical outcomes –14. The Patients who underwent baseline and follow-up coronary OCT examinations at the Second Affiliated Hospital of Harbin Medical University September 2013 to December 2018 were retrospectively enrolled in current study. Decisions to perform OCT examinations and detailed scanning vessels were decided by the operators during percutaneous coronary intervention (PCI). The main inclusion criteria were as follows: (1) patients diagnosed as ACS at baseline, including STEMI and non-ST-segment elevation acute coronary syndrome ; (2) TimBaseline and 1-year follow-up clinical data, including demographic characteristics, cardiovascular risk factors, results of laboratory specimens, medications were obtained from the electronic medical record system of our hospital. The achieved lipid levels were collected and tested from the fasting venous blood samples during hospitalization of 1-year follow-up.2, FCT < 75 µm, maximum lipid arc >180° and OCT-defined macrophages  and compared with Mann–Whitney U-test. Categorical variables have been shown as absolute frequencies (relative percentages) and compared with the Chi-square test or Fisher's exact test. Kappa test was conducted to assess the intra- and inter-observer agreement. Pearson correlation analysis and partial correlations analysis were used to examine the associations of serum lipid levels with OCT-detected plaque evolutions. The area under the curve (AUC) was compared using receiver operating characteristic (ROC) analysis to determine the best cut-off value of aLHR to be used for predicting lesion regression within 1 year. To account for the potential effects of clustering of multiple non-culprit lipid-rich plaques in a single patient, generalized estimating equations were used to identify independent predictors for vulnerable plaque phenotypes at 1 year. A two-sided p < 0.05 was considered statistically significant.The SPSS 26.0  was used for statistical analysis. Continuous variables were tested for normality with the Kolmogorov–Smirnov test. Normally distributed variables were reported as mean ± standard deviation (SD) and compared with the Student's p = 0.920).Between September 2013 and December 2018, a total of 132 ACS patients with 215 non-culprit lipid-rich plaques were taken into final analysis. According to the median value of the aLHR , patients were divided into the low aLHR group and the high aLHR group separately. The median follow-up time duration of overall subjects was 366.5 (from 285 to 443) days, which was comparable between the two groups . Five patients didn't have pre-dilation OCT images of the culprit vessel. Culprit lesion etiology was comparable between the two groups in 127 patients with analyzable culprit OCT images (p = 0.390), including 86 with plaque ruptures, 34 with plaque erosions, 2 with severe stenosis and 5 with in-stent restenosis.Baseline demographic characteristics, cardiovascular risk factors and medications at discharge was shown in As for the lipid lowering therapy, 98.5% (130 of 132) patients received statins medications at discharge, including 86 cases with atorvastatin 20 mg/day and 44 cases with rosuvastatin 10 mg/day. The detailed category and intensity of statins were similar between the high aLHR group and the low aLHR group. 127 of 132 patients were ongoing statins when re-assessed the lipid profile at 1-year follow-up, resulting a 3.8% of statin discontinuation (4 patients in the high aLHR group and 1 patient in the low aLHR group).Almost all patients received dual anti-platelet therapy (aspirin plus ticagrelor or clopidogrel) at discharge, the rate of which was comparable between the two groups. Overall, 56.8% of patients were discharged on beta-blockers and 60.6% on angiotensin converting enzyme inhibitor or angiotensin receptor blocker, which were also similar between groups.p < 0.001) in the high aLHR group. Within 1 year after discharge, the overall proatherogenic lipid levels in both groups improved to a certain extent. Patients with low aLHR showed more reduction in total cholesterol, triglycerides and LHR, when compared with those with high aLHR . A higher tendency in the reduction of LDL-C was also observed in the low aLHR group. At 1-year follow-up, all indicators of serum lipids in the high aLHR group were significantly higher than those with low aLHR.The result of serum lipid levels was shown in p = 0.924). Among the 215 lipid-rich plaques, 84 (39.1%) located in the right coronary artery, 83 (38.6%) in the left anterior descending artery and 48 (22.3%) in the left circumflex artery. 38.6% of the non-culprit lipid-rich plaques located in the culprit artery. The distribution of lesion locations was similar between the high and low aLHR groups. With respect to luminal characteristics and lipid components, such as lumen area, area stenosis, lesion length, lipid arc and FCT, there were no statistically significant difference between the two groups. Furthermore, microstructures were also comparable, except a higher prevalence of microchannel  and a higher tendency of spotty calcification  in the high aLHR group.Baseline angiographic and OCT characteristics of the targeted lipid-rich plaques was listed in p = 0.025) in patients with high aLHR. Besides, there were higher incidences of TCFA  and CLIMA-defined high-risk plaques  in the high aLHR group. Luminal characteristics, lipid arc and lipid length were comparable between the two groups.1-year OCT findings were listed in p = 0.001), maximal lipid arc  and lipid index . Meanwhile, patients with low aLHR showed apparently better increasement of FCT  within 1 year. There were no significant differences between the two groups in terms of luminal changes.The changes in quantitative OCT parameters were illustrated in r = 0.246; p < 0.001), ▵maximal lipid arc , ▵FCT , ▵lipid length , ▵lipid index  and 1-year FCT .Changes in vulnerable features of the lipid-rich plaques with baseline and follow-up serum lipid levels were tested for simple linear correlations analysis  and partp = 0.001]. Coincidentally, the best cut-off value of aLHR to predict the reduction of FCT >0 µm was also 1.51 .Using ROCs, the best cut-off value of aLHR to predict the increasement of maximal lipid arc ≥0° was 1.51  during 1-year OCT examination. There were larger maximal lipid arc, lipid length and thinner FCT in patients with aLHR ≥1.51 than those with aLHR <1.51 at 1 year : 3.008, 95% CI: 1.370 to 6.605, t 1 year .The relationship between baseline LHR and major adverse cardiovascular events has been investigated in ACS patients after percutaneous coronary intervention . HoweverPrevious studies mainly focused on the impact of baseline serum lipid levels on clinical prognosis, which is undoubtedly a very important aspect , 21. HowAccounting for approximately two thirds of plasma cholesterol, LDL-C has been recognized as the primary driver of atherogenesis . HDL-C wIn addition to LDL-C, HDL-C and the derived LHR, progression or regression of coronary atheroma was also influenced by other lipoproteins. The EVAPORATE trial proved that eicosapentaenoic acid could impact plaque changes in those with elevated triglycerides on statin therapy, indicating effect of triglyceride on plaque composition . In curr2, FCT <75 µm, maximum lipid arc >180° and macrophages were strongly associated with increased risk of major cardiovascular events at 1-year follow-up , we found aLHR was the strongest predictor of plaque progression and vulnerable plaque phenotype at 1 year. Kurabayashi et al. suggested the target index for regression of atherosclerosis should be less than 2.0 for primary prevention and less than 1.5 for secondary prevention . Based oAs one of the most important secondary cardiovascular prevention targets, adequate lipid control was still not achieved in majority of ACS, highlights the urgent necessity of whole-process lipid management . Our datNotably, the protective effect of HDL-C in its extremely high levels is controversial. A large-scale Japanese cohort study revealed that approximately 1.5% of individuals exhibit an extremely high HDL-C level (≥2.33 mmol/L), and they were associated with adverse outcomes . CoincidFirst of all, as a retrospective single-center study, potential bias in patient and lesion selection was inevitable. Only patients survived and finished OCT scan at follow-up were enrolled in this study. We adjusted for age, gender, cardiovascular risk factors and statins at discharge to diminish the possible influences of confounders in the generalized estimating equations. In addition, the intervention of lifestyles also influent the evolution of targeted plaques, and some of these data was not available in this study for retrospective reasons. Besides, only patients with non-culprit lipid-rich plaques were enrolled into analysis. The effects of aLHR on fibrous and calcified plaques needs further exploration. Fourth, the lipid lowering therapy of most enrolled patients were moderate-intensity statins, and none of them received high-intensity statins or PCSK9 inhibitors in current study. This may attribute to the genetic differences of Chinese population in genetics and weight, and the clinical practice at discharge. Further studies were warranted to explore the application of aLHR in patients with different dose of statins or PCSK9 inhibitors. Fifth, limited by the relatively small sample size, the impact of kidney function on the change of plaque components  was not analyzed in detail in current study.In this serial OCT study focusing on the impact of aLHR on the evolution of lipid-rich plaques in ACS, patients with higher aLHR showed more aggressive changes in lipid components and more vulnerable plaque phenotype at 1-year follow-up. These findings highlight the importance of standardized aLHR control and provided evidence for individualized secondary prevention of ACS.